Aza-Cope Rearrangement-Mannich Cyclizations for the Formation of Complex Tricyclic Amines: Stereocontrolled Total Synthesis of (+-)-Gelsemine

摘要

A detailed examination of the use of aza-Cope rearrangement-Mannich cyclization sequences for assembling the azatricyclo[4.4.0.0~(2,8)]decane core of gelsemine is described.Iminium ions and N-acyloxyiminium ions derived from endo-oriented 1-methoxy- or 1-hydroxybicyclo[2.2.2]oct-5-enylamines do not undergo the first step of this sequence,cationic aza-Cope rearrangement,to form cis-hydroiso-quinolinium ions.However,the analogous base-promoted oxy-aza-Cope rearrangement does take place to form cis-hydroisoquinolones containing functionality that allows iminium ions or N-acyloxyiminium ions to be generated regioselectively in a subsequent step.Mannich cyclization of cis-hydroisoquinolones prepared in this way efficiently assembles the azatricyclo[4.4.0.0~(2,8)]decane unit of gelsemine.Using a sequential base-promoted oxy-aza-Cope rearrangement/Mannich cyclization sequence,gram quantities of azatricyclo[4.4.0.0~(2,8)]decanone 18,a central intermediate in our total of (+-)-gelsemine,were prepared from 3-methylanisole in 12 steps and 16% overall yield.